JPS59111736A - Dialytic probe - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Living tissues consist of cells living in a fluid environment that transports nutrients and degradation products to and from the cells and adjacent blood vessels. Through this extracellular fluid space,
All the building blocks necessary for the metabolism of individual cells are transported, but also all the signaling substances that signal the cells of the body's needs. 'Examples of such signal substances are hormones such as insulin, estrogen and others. A particularly important form of transport occurs in the nervous system. Electrical nerve pulses emit signal substances (transmitter ducts) that flow from the terminals of one neuron to the male ducts of other neurons that immediately carry the receiving molecules. Brain function as a whole is the result of the emissions of these transmitter tracts. Therefore,
Brain diseases are assumed to be due to disturbances in the output of the transmitter tract, and the drugs with which brain disease patients are treated are known to affect these substances.

In order to understand the functions of the body, it is especially important to be able to follow the "transport" of substances between the body's cells and between cells and blood vessels. Traditionally, this has been done by extracting the blood and analyzing its contents, or by sparging the blood vessels with physiological fluids and then examining their content. However, these methods only give indirect indications of the intercellular environment and are also difficult to apply to many male tubes. This is especially true in the brain, where it cannot be distributed to blood vessels that go to certain defined areas. Therefore, attempts were made to develop new techniques, such as the so-called Husch-pull technique, in which two tubes are inserted into the brain and fluid is forced through one and the same amount is withdrawn through the other. U.M.J.

H. (1961), J. Physiol, 155
, 1-2) In this way, the small depressions created at the end of the tube are washed out and chemicals from the adjacent cells are extracted with the fluid, which can then be analyzed for its contents. reversibly injected and extracted;
The problems involved in simultaneously ensuring that the surrounding environment does not pose a risk of injury are obvious. Research has also had difficulty applying this technique to small test animals.

Another known way of sampling the contents of the extracellular space is to apply the dialysis principle.

In tissue dialysis, a dialysis membrane and conduits for the flow of a dissemination fluid over the membrane are inserted into the tissue such that the dissemination fluid flows over the membrane and is then collected for chemical analysis. Such tissue dialysis can be performed in essentially all tissues. Dialysis is performed in a defined area, causes very little trauma, is methodologically simple to perform, and is particularly suited to the study of brain functioning. Known dialysis probes for this purpose consist of two conduits running side by side in the form of a push-pull cannula, terminating at the distal ends in a small sac of permeable material. , whose sack is a dialysis membrane (DE-LGADO, J., M., R., et al. (1972))
, Aioh int de Ph-armacoc
l et de Theropie, 198, 1,
9-21), or the conduit for the dispensing fluid is in the form of two successively placed conduit sections, which are also in the form of a hose, so that the two The conduit-forming hose parts are joined together and curved into a horseshoe shape. (Vngsrstedt,
U. et al. (1982).

Advances in the Biosciences
es+37, 219-231, 0xford an
d New York: Kohsaka, M et al. (eds.)
.

However, both of these known dialysis probes have significant drawbacks. In addition to being difficult to locate, membranes have the disadvantage of being poorly defined in terms of effective dialysis surface area and properties. Also,
It is also difficult to ensure correct fluid flow through the membrane.

With sac-shaped membranes, there is a potential risk that one or the other of the conduit openings inside the membrane will become blocked by the membrane's own combustible wall material. Tubular membranes, which can be hollow fibers, can be easily deformed and the flow conduits can be closed off as soon as the membrane is bent. Therefore, to keep the membrane open, microstructures should be placed within it.

In order to place a probe with a tubular membrane on the upper mold,
The inside of the membrane requires some type of additional support means when it is placed in place. This support means must then be removed before the probe is used.

Provided that suitable dialysis probes can be manufactured that avoid the drawbacks mentioned here in known probes, such dialysis techniques may be useful in various metabolic processes, such as in monitoring brain status after cranial trauma. There should be important clinical use in measuring oxygen and glucose metabolism. With the help of appropriate isotopes, various aspects of brain function can be followed as well.

In cytotoxin treatment, dialysis can also be used to monitor the amount of cytotoxin reaching the tumor or being received by normal tissues. It should also be possible to administer the cytotoxin locally by reverse dialysis, whereby the cytotoxin leaves the dialysis fluid and percolates into the tissue to be treated. In both clinical and research settings, the penetration of drugs into the brain and other tissues can be investigated using this dialysis method. Dialysis can of course also be used for organs other than the brain, i.e. to study liver function, for example to study muscle metabolism, cardiac metabolism during and after surgery, to drill into tumors for diagnosis and treatment. It may also be used in many intensive care situations where fluid status and metabolism can be followed subcutaneously or in body organs or cavities. A suitable dialysis probe can also be inserted into a blood vessel to continuously monitor blood status without the need to draw blood from the patient. The probe may also be used in various in vitro situations, such as sampling metabolic products in various cell cultures, fermentation vessels, and the like. The dialysate is then transferred to a chemical laboratory for analysis or, if appropriate, connected directly to a suitable measuring device.

The present invention relates to a dialysis probe of the known type described herein, which includes a dialysis membrane and conduits for the flow of a dispensing fluid over the membrane.

The purpose of the present invention is to propose a new and improved probe based on such a probe, originally intended for use in inserting living tissue, and which does not have the drawbacks mentioned above. . Furthermore, the new and improved probe should enable routine use of tissue dialysis techniques, both in clinical and preclinical research, without limiting its application to living tissue. No. Various embodiments should be available for use in various research fields, from humans to large test animals, and in small test animals.

The dialysis probe made according to the present invention has been proven to meet this purpose in tests in small animal tissues, and its original feature is that the dialysis probe supports the membrane and partially The membrane is exposed and is surrounded by a device that is more rigid than the membrane. The membrane fitting in a dialysis probe constructed according to the present invention is more rigid than the membrane itself, thereby supporting and protecting the membrane, and furthermore, only a portion of the membrane is exposed. Because there are
Due to the fact that the size and shape of the part of the membrane involved in dialysis can be adapted to the size and shape of the tissue location to be studied, the probe according to the invention
It is also sturdy and quite easy to handle, as well as being easy to insert and hang for use. As a result of the well-defined shape and size of the membrane parts participating in dialysis, it can be used with directed effect.

Tips made according to the invention can have many unusual shapes, from more or less spherical to elongated.

In an embodiment that is particularly useful for dialysis of brain tissue, and which is versatile and at the same time relatively simple and inexpensive to manufacture, the dialysis membrane and the device are capable of attaching the membrane at least partially to the membrane. It is inserted into the tube and is tubular in nature. This construction gives the probe an elongated, relatively easily applied, bell-shaped profile and allows the dialysis membrane to have its distal end freely exposed and protruding from the fitting, or alternatively, allows the dialysis membrane to have its distal end freely exposed and protruding from the fitting. You can also make it completely contained inside. In the first case, the externally exposed part involved in the dialysis membrane is at the distal end of the probe, while in the latter case the relevant membrane is more than one in the wall of the appliance. (exposed through the opening).

In both cases, the distal ends of both the dialysis membrane and the fitting are sealed. In the latter case, the seals at these ends may be common to the dialysis membrane and the device.

The distal end of the probe can be appropriately rounded to avoid undue tissue damage. In some cases, however, it may be advantageous to make the tip of the probe pointy to facilitate installation at the site of use. For the same reason, the end can also be provided with a cutting edge, possibly sharpened. Yes 1. The probe according to the invention can be inserted into a blood vessel or tissue in the same manner as a cannula.

In a particularly advantageous embodiment of the dialysis probe according to the invention, the conduit for flowing the dispensing fluid to the membrane can be accessed from the outside of the proximal end of the probe. They can be made to protrude from the end and possibly be surrounded by an extra protective casing. If the conduits accessible at the tip of the probe can be of any different type and have means for connection to the necessary equipment for the dialysis process not covered by the invention. and significant advantages are obtained. The connection between this device and the probe according to the invention is preferably
It should consist of one or more conduits of suitable dimensions. The coupling device at the distal end of the probe may extend axially from tip to tip, or in probes constructed according to the invention in which at least one of the coupling devices extends more or less radially from the tip. To ensure the best possible spray fluid flow over the part of the membrane participating in dialysis, one of the fluid grooves has its opening at the distal end of the part of the membrane exposed by the fitting. Hold it inside a probe placed nearby.

The second conduit, on the other hand, has its opening inside a probe placed near the proximal end of this membrane section. If a conduit is opened near the proximal end of the exposed membrane section and consists of an open space inside the probe, within which space a conduit whose opening is near the proximal end of the membrane section is inserted. A particularly simple embodiment is obtained if it is made of elongated material. (Thus, only one conduit element is used, while the other conduit is formed by an open space in the probe surrounded by a membrane fitting. This conduit-forming closure inside the probe Suitably, the space communicates with a coupling device extending laterally from the probe in the form of a pipe socket or the like.

The invention will be explained in more detail below with reference to two embodiments shown in the accompanying figures for dialysis probes made according to the invention.

Dialysis probes made according to the invention can have very small dimensions, for example in the case of brain tissue dialysis, only fractions of a millimeter.

As can be seen from the foregoing, and as shown in the figures, the probe constructed in accordance with the present invention consists of a dialysis membrane with conduits associated with it to effectuate the flow of the dispensing fluid over the membrane. In principle, this can be constructed in any suitable manner,
The number and shape of conduits may also vary. The only critical factor is that the necessary flow of sparging fluid must be maintained over the portions of the membrane participating in dialysis.

In the two embodiments shown here for the probe according to the invention, the dialysis membrane 1 is essentially tubular, which has proven to be advantageous both in terms of function and manufacturing. According to the invention, the membrane is surrounded by a fitting 2 which supports the membrane and is partially exposed and is more rigid than the membrane I. In addition to providing support to the membrane 1, the attachment also protects the membrane.
Thereby, the probe according to the invention is quite affordable, which is advantageous both for its manufacture and also for its storage and use. In the two embodiments shown, the fitting 2 is essentially tubular and consists of a thin-walled metal sleeve of vine shape and inner diameter into which the tubular dialysis membrane 1 is inserted. ing. In order to have the necessary dialysis properties, I
The J Samurai 1 itself is constructed of a suitable thin-walled permeable hose material. The structure utilizes readily available "hollow fibers" that are available in a variety of sizes with different dialysis properties to suit specific applications of single-tissue dialysis. The membrane is then easily inserted into the external support tube.

The probe embodiment shown in Figures 1-3 was originally intended for human use, in which the dialysis membrane l is inserted in its entirety into a fitting 2 consisting of a metal sleeve. There is an opening 3 in the wall, in which a part of the vague surface is exposed.

The size and shape of the openings 3 may be varied accordingly to the size and shape of the dialysis surface of the membrane. The membrane 1 is inserted into the appliance as close as possible to the walls of the appliance. The proximal ends of both the dialysis membrane and the fitting are sealed, for example with epoxy, such that the tubular membrane is also sealed to the fitting. The seal at the proximal end of the probe is suitably matched to the shape of the device and can vary in shape from abruptly cut to sharply cut like a syringe cannula. In the probe shown in Figure 1, the seal is rounded to prevent undue damage to the tissue.

In the probe embodiment shown in FIGS. 4-6, which was originally intended for use in laboratory animals, the tubular dialysis membrane 1 is placed only partially in a fitting, which also consists of a tubular metal sleeve. Once inserted, the proximal end of the membrane freely projects from the appliance. In order to be firmly fixed and carefully sealed to the fitting, the proximal end of the membrane is pasted into the fitting, for example with epoxy resin 5. The proximal end of the membrane is cut into squares and sealed with, for example, an epoxy plug 6.

In most embodiments of the diffusion probe according to the invention, the conduits for the flow of the dispensing fluid onto the membrane should be accessible from outside the proximal end of the probe.

In the two embodiments shown herein, there is a device that connects the dispensing fluid conduits to the rest of the dialysis machine at the proximal end. These devices consist of protruding tubular connecting pieces 7, 8 and 9. It consists of lO. In the embodiment shown in Figure 1, these pieces extend axially from the tip to it in direct continuation of the conduit extending inside the membrane. In the embodiment shown in FIG. 4, only one connecting piece 9
extends from the probe in the axial direction, while the other 10
extends in the radial direction. This arrangement of dispensing fluid conduit connections pointing in different directions has significant practical advantages in connection with laboratory animals.

As can be seen from the above, the connecting pieces 7 to 10 projecting from the probe according to the invention are the projecting parts of the conduit necessary to achieve the flow of the dispensing fluid past the dialysis surface of the membrane 1. It should be taken into account. In the embodiment shown in FIG. 1, there are two conduits 11.12 for dispensing fluid flow. Both have the form of thin-walled metal tubes, which protrude through seals 13, for example made of epoxy resin, which seal the proximal ends of both the membrane 1 and the fitting 2. The protruding ends of these two metal tubes form the connecting piece 7.8 over which the dual-conduit catheter 14 is slid to connect the probe to the rest of the dialysis machine. It is. Two metal tubes or conduits 11, 12 have diameters such that they fit inside the probe, one conduit 11 having its opening at the proximal end of the portion of membrane 1 delivered by the fitting. is located near the other conduit 1.
2 has its aperture inside a probe placed near the proximal end of the membrane section. The longer of the two conduits 11.12 is intended for introducing the spraying fluid, while the shorter conduit is intended for withdrawing the fluid.

A probe of the type shown in Figure 1 can be inserted into living tissue through an intravenous cannula-type insertion tube, in which the internal cannula is removed, replaced by the probe, and then removed. It is suitably connected to a flammable hose 14 and adapted to the movement of the tissue in question.

In the embodiment shown in FIG. 4, there are two conduits 15, 16 for the circulation of the spray fluid through the probe. A conduit 164 with a 14" opening near the proximal end is formed by an open annular space inside the probe. This space has its opening 14" close to the proximal end of the membrane. , which is in open communication with a piece of tube 10 extending laterally from the probe, while another conduit 15, suitably made of a metal tube, projects from the probe, The end that forms the axial connection piece of the probe is attached.Appropriate number is attached to the proximal end of the probe +1
The fluid conduit 15, consisting of a metal tube, is sealed with, for example, an epoxy TL 115 plug and the two conduits 15.16 long (1. lead to the end, where the conduit 15 force (opens).

The fluid then flows up between the wall of the membrane 1 and the outside of the conduit 15, and the actual dialysis occurs. Closer to the proximal end of the probe, the fluid rises through the annular conduit 16 and finally
It is pulled out from the probe through a connecting piece 10 that projects in the radial direction C.

In this type of probe according to the invention, the size of the dialysis surface can be varied by adapting the part of the membrane l exposed on the outside of the fitting 2.

This probe, originally intended to be inserted into the brain of a laboratory animal, is inserted through a hole made in the skull. The probe is fixed to the surface of the skull with a suitable adhesive such as dental cement.

The invention is not limited to the two embodiments described here and shown in the figures, but may be modified in many ways within the scope of the claims.

[Brief explanation of the drawing]

FIG. 1 shows an axial section of a probe originally intended for human use. 2 and 3 show cross-sections of the same article along lines 1--1t and 11 of FIG. 1, respectively). FIG. 4 shows an axial section corresponding to FIG. 451 of a probe chamber according to the invention originally intended for use in laboratory animals. Figures 5 and 6 show the lines v-v and W-V in this variant.
A cross section along l is shown. For clarity, all figures are shown on an enlarged scale. Patent Applicant Rikiruru Urban Ungerstedt Agent Hikaru Adachi Shiima
Satoshi Adachi FIG, I
FIG, 2 "■ FIG, 4 HiIG, ':)

Claims (1)

[Scope of Claims] 1. A dialysis membrane (1) and a conduit (11, 1205, 16) for flowing a dispensing fluid over the membrane, which is originally intended to be inserted into a living tissue such as a brain tissue. ) and consists of
The dialysis membrane (1) is a dialysis probe characterized in that it is surrounded by an attachment (21) that is more rigid than the membrane and that supports and partially exposes the membrane. 2. Dialysis membrane fi+ A dialysis probe according to claim 1, characterized in that both the and the attachment (2) are essentially tubular, and the probe is at least partially inserted into the attachment. 3. The dialysis probe according to claim 2, wherein the distal end of the dialysis membrane [11] protrudes from the attachment (25) and is exposed (FIG. 4). 46 The dialysis membrane (1) is inserted in its entirety into the attachment (2), and there is an opening (31) in the wall of the attachment, in which a part of the surface of the membrane is exposed (first 5. The dialysis probe according to claim 2, characterized in that it is configured as shown in Figure 2.5. The dialysis probe according to claim 3 or 4, characterized in that the distal ends of both the dialysis membrane and the attachment are sealed by a common sealing device (4). 7. Dialysis probe according to claims @4 and 5, characterized in that the distal end thereof is rounded (FIG. 1). 8. A dialysis probe according to one or more of the following claims. 8. A dialysis probe according to claims 1 to 8, characterized in that the distal end thereof is provided with a cutting edge, which may be pointed. Dialysis probe as described in one or more of paragraphs 6. 9. Conduit (11° 12
115.16) is accessible from the outside of the proximal end of the probe (FIGS. 1 and 4). dialysis probe. 10. The dialysis probe according to claim 1θ, characterized in that the conduits protrude from the proximal end of the probe (FIGS. 1 and 4). 11, the proximal end of the probe is connected to the conduit (11, 12115, 16
) to the rest of the dialysis machine (7°8; 9
, 10). The dialysis probe according to claim 1O, characterized in that it has: 12. Dialysis probe according to claim 12, characterized in that the connecting device (7, 8) projects from the probe in its axial direction. 13. At least one (lO) connection device (9°10
13. Dialysis probe according to claim 12, characterized in that the dialysis probe (FIG. 4) projects more or less radially from the probe towards it. 14. A conduit (11) carrying the dispensing fluid over the membrane has its opening inside the probe placed near the unabated end of the portion of the membrane exposed by the mounting device (21). , on the other hand, the other conduit (12) is characterized in that it has its opening inside a probe placed near the distal end of the membrane part. The dialysis probe according to one or more of the above: 15. The conduit (16), the opening of which is placed in the vicinity of the open end of the exposed membrane portion, consists of an open space inside the probe; 16. A dialysis probe according to claim 15, characterized in that a conduit extends into the space and has an opening in the vicinity of the distal end of the membrane section.16. The inner conduit-forming open space (16) is characterized in that it communicates with a connecting device (FIG. 4) projecting laterally from the probe, in the form of a pipe socket or the like (1o). A dialysis probe according to claim 16.